A NOVEL, LOGICAL APPROACH TO HIV VACCINE DEVELOPMENT

描述：（改编自申请人的摘要）我们将从根本上追求 艾滋病毒疫苗设计的不同方法。艾滋病毒感染者的治疗 单一的抗逆转录病毒药物往往导致变异的出现， 抗药性病毒我们最近发现细胞免疫反应 对病毒施加类似的选择性压力。我们将设计候选人 通过识别这些区域的病毒在强烈的选择性 急性SIV感染期间的压力。我们会在4点对整个病毒进行测序， 感染后16周，以确定细胞免疫反应， 在控制早期病毒复制方面很重要。我们的假设是 产生选择压力细胞毒性T淋巴细胞（CTL）的疫苗诱导 将减少在猕猴中的初始病毒复制， SIV为了解决这个假设，我们首先需要知道哪个CTL 反应控制病毒复制。在具体目标I中，我们将对 在感染后2、4和16周，来自12只猕猴的整个SIV病毒基因组 用分子克隆的病毒来鉴定病毒的区域， 逃跑了我们将使用一组重叠的肽， SIVmac239基因组用于绘制这些感染动物的细胞免疫反应 使用ELISPOT测定。在《特定目标II》中，我们将给猕猴接种 病毒中未被免疫反应识别的区域。我们 已经有初步数据表明，病毒分离4周 感染后已经从强CTL应答中"逃脱"。这表明 负责选择逃逸变体的CTL已经破坏了所有细胞 积极生产野生型病毒。因此，我们将使用表位在 野生型病毒在急性感染期间逃逸以诱导强CTL。我们 预测这些疫苗诱导的CTL应答将减少最初的 病毒血症，并防止逃逸突变体的产生，从而促进 产生强烈的宿主免疫反应。这一提议的结果 利用SIV攻击的恒河猴， 艾滋病疫苗的合理设计如果接种病毒区域 在急性期的逃逸减少了猕猴最初的病毒血症，那么我们 可以在疫苗接种方案中使用HIV中的类似区域。事实上， 基于表位的疫苗已经在牛津和肯尼亚进行了I期试验， 麦克迈克尔博士的方向因此，我们的研究结果将 对疫苗的最终设计至关重要。

DESCRIPTION: (Adapted from Applicant's Abstract) We will pursue a radically different approach to HIV vaccine design. Treatment of HIV-infected patients with single antiretroviral drugs often results in the emergence of variant, drug-resistant viruses. We have recently shown that cellular immune responses place similar selective pressure on the virus. We will design candidate vaccines by identifying those regions of the virus under intense selective pressure during acute SIV infection. We will sequence the entire virus at 4 and 16 weeks post-infection to determine cellular immune responses that are important in controlling early viral replication. Our hypothesis is that vaccine-induction of cytotoxic T lymphocyte (CTL) that exert selective pressure on the virus will reduce initial virus replication in macaques challenged with SIV. To address this hypothesis we first need to know which of the CTL responses control virus replication. In Specific Aim I we will sequence the entire SIV viral genome from 12 macaques at 2, 4 and 16 weeks post-infection with a molecularly cloned virus to identify regions of the virus, which have escaped. We will use an overlapping set of peptides spanning the entire SIVmac239 genome to map cellular immune responsesin these infected animals using ELISPOT assays. In Specific Aim IIwe will then vaccinate macaqueswith the regions of the virus that have escaped recognition by the immune response. We already have preliminary data suggesting that virus isolated 4 weeks post-infection has "escaped" from a strong CTL response. This suggests that the CTL responsible for selecting the escape variants had destroyed all cells actively producing the wild-type virus. We will, therefore, use epitopes in the wild-type virus that escape during acute infection to induce robust CTL. We predict that these vaccine-induced CTL responses will reduce the initial viremia, and prevent escape mutant generation, thereby facilitating the development of strong host immune responses. The results of this proposal utilizing rhesus macaques challenged with SIV will have direct relevance to the rational design of a vaccine for HIV. If vaccination with regions of the virus that escape during the acute phase reduce initial viremia in macaques, then we can use analogous regions in HIV in vaccination regimens. Indeed, a CTL epitope-based vaccine is already in Phase I trials in Oxford and Kenya under the direction of Dr. McMichael. Thus, results from our studies will be important in the eventual design of this vaccine.